CYP2E1 and catalase influence ethanol sensitivity in the central nervous system.

摘要

OBJECTIVES: Genetic factors are known to influence the sensitivity and tolerance to ethanol in humans and laboratory animals. Ethanol is metabolized to acetaldehyde mainly by the alcohol dehydrogenase pathway (ADHs) and, to a lesser extent, by microsomal oxidization (CYP2E1) and the catalase-H2O2 system. METHODS: In this study, we examined the role of CYP2E1 and catalase in ethanol metabolism and sensitivity, using transgenic knockout Cyp2e1(-/-) mice, acatalasemic (Cs/Cs) mice, double mutant Cyp2e1(-/-)/Cs/Cs mice and their respective wild-type counterparts 129/sv, C3H/HeJ, 129/sv X C3H/HeJ mice. Ethanol was administered to the mouse lines and ethanol pharmacokinetics and sleep times were evaluated. RESULTS: Although the rates of whole blood ethanol elimination following i.p. administration were found to be similar regardless of dose or genetic stock, Cs/Cs, Cyp2e1(-/-) and Cyp2e1(-/-)/Cs/Cs mice exhibited longer ethanol-induced sleep times, especially at higher ethanol doses. This infers that there is less acetaldehyde produced in the brains of these animals and is in opposition to the idea that increased acetaldehyde increases the actions of ethanol. The Cyp2e1(-/-) animals produced lower whole blood levels of acetaldehyde than wild-type controls; however, this difference was seen only at higher doses of ethanol. The amount of acetaldehyde produced following the incubation of ethanol with liver and brain microsomes was greater in tissues derived from 129/sv than in those from Cyp2e1(-/-) mice. CONCLUSIONS: Although the contribution of CYP2E1 and catalase in ethanol oxidation may be of little significance, these enzymes appear to play a significant role in ethanol sensitivity in the brain.